Parkinson's disease (PD) is an age-related neurodegenerative disorder typified by selective loss of nigrostriatal dopaminergic neurons. The etiology of Parkinson's disease is currently unknown but hypothesized to involve both genetic vulnerability and environmental toxicants. Despite disparate initiating factors a shared biochemical pathway is posited to elicit a phenotypically similar clinical syndrome and neuropathological state. This convergent pathophysiological hypothesis asserts that specific downstream biochemical pathways mediate the synaptic loss, cellular injury, and death observed in Parkinson's disease. We posit that these pathophysiological changes will be manifest in peripheral compartments, which share these signaling pathways. Specifically, we propose that peripheral leukocytes will report the PD pathogenic process and will be reflected in alterations in protein levels and functions. As such, these changes will serve as important biomarkers for PD diagnosis and progression and will provide valuable insights into its pathophysiology and potential therapeutics. We propose to utilize exploratory approaches on human peripheral leukocytes within select clinical populations, coupled with directed methodologies for validation. In the proposed study we will use an exploratory proteomics approach to provisionally identify differential protein expression in leukocytes from patients with PD (non-demented), late onset Alzheimer's disease (LOAD), mild cognitive impairment (MCI) and from age-matched control (non-demented) subjects. We currently have leukocyte protein samples from a total of 12 subjects per group and all subjects have been well characterized with respect to clinical stage and neuropsychological testing. 2-dimensional gels have been completed for these samples. In this study we will use computer-based analysis (Progenesis software) to identify differentially expressed proteins. Furthermore, we propose to sample an additional 13 subjects/group for a total number of 25 subjects in each of the four groups. Following exploratory analyses, these profiles will be validated using standard proteomics methods in the initial cohort as well as in a separate cohort of PD and control subjects (15 subjects each). We currently have leukocyte samples from all 30 subjects in this second cohon and prepared to validate identified biomarkers. We hypothesize that these approaches will in aggregate identify profiles of proteins within peripheral leukocytes that will categorize PD subjects from non-PD subjects. We believe that these unique and innovative studies will provide a wealth of proleomics information that will translate to improved PD diagnosis and evaluation of therapeutic interventions. [unreadable] [unreadable]